The worker response to the World Trade Center (WTC) attacks was unprecedented in scope, involving tens of thousands of traditional and non-traditional responders in rescue, recovery, and clean-up efforts. Posttraumatic stress disorder (PTSD) arising in response to equally unprecedented traumatic exposures, and characterized by disabling intrusive memories of the disaster, repeated nightmares, avoidance of disaster reminders, increased fear of another attack, disrupted sleep and other symptoms, is both highly prevalent (about 14%) and persistent in WTC responders, even over a decade after 9/11. The proposed study aims to fill a major gap in our understanding of the development of this disabling condition by conducting a multi-level assessment of vulnerability to PTSD in a diverse sample of 500 professional (i.e., police) and non-traditional (i.e., construction workers) WTC responders recruited from a large responder cohort followed prospectively at the WTC Medical Monitoring and Treatment Program (WTC- MMTP) at the Mount Sinai School of Medicine. We have previously identified four distinct trajectories of PTSD symptoms over time in this cohort of over 10,000 responders: chronic PTSD, delayed-onset PTSD, recovering and resistant trajectories. In this project we will study 500 WTC responders (125 selected from each of the four trajectories) to identify a range of exposure, psychological and biological factors that distinguis responders in the four trajectories. This assessment will include in-person psychiatric, medical, cognitive and psychosocial evaluations, as well as collection of blood and urine samples for testing. Testing will include (1) measurement of cortisol and its metabolites in urine; (2) measurement of cortisol and adrenocorticotropin hormone (ACTH) levels in blood before and after administration of a steroid, dexamethasone (dexamethasone suppression test); (3) measurement of the inhibition of lysozyme synthesis in blood cells by dexamethasone, and index of glucocorticoid receptor sensitivity in blood cells; (4) the identification of gene variant associated with increased risk for PTSD; (5) measurement of the expression levels of two different genes previously found to be associated with risk for PTSD -the gene coding for the glucocorticoid receptor (GR) and the gene coding for FKBP5, a modulator of GR sensitivity-; and (6) measurement of methylation levels of the GR and FKBP5 genes (a mechanism by which environmental influences such as traumatic experiences can modify genetic effects). The goal of the study is to further the field's understanding of PTSD risk and protective factors in disaster responders with varying degrees of preparedness and training in disaster response. Findings on risk factors can be used to improve future prevention and treatment strategies, while findings on protective factors can be applied to bolster resilience in rescue and recovery workers prior to trauma exposure. PUBLIC HEALTH RELEVANCE: Posttraumatic stress disorder (PTSD) arising in response to the World Trade Center (WTC) disaster is one of the most prevalent and persistent psychiatric disorders among workers involved in rescue, recovery, and clean-up efforts in response to this disaster, even several years after 9/11. The proposed study will employ a multi-level approach to study clinical, psychosocial, neuroendocrine, genotypic, gene-environment interaction, and molecular factors associated with PTSD risk and resilience in a sample of 500 WTC responders selected from a cohort of over 10,000 responders exhibiting four distinct longitudinal PTSD symptom trajectories: chronic PTSD, delayed-onset PTSD, recovering, and resistant trajectories. Findings on risk factors can be used to improve future prevention and treatment strategies, while findings on protective factors can be applied to bolster resilience in rescue and recovery workers prior to trauma exposure.